Studies of consomic mice bearing the Y chromosome of the BXSB mouse.

Previous studies have demonstrated that the Y chromosome of the BXSB mouse can lead to accelerated autoimmunity in inbred BXSB mice and in F1 hybrids. To additionally study the effects of the BXSB-Y, we have studied three sets of Y-consomic mice, NZB.BXSB-Y, NZW.BXSB-Y, and CBA/J.BXSB-Y, each consisting of background genes from the non-BXSB parent and the Y chromosome from the BXSB mouse. The effect of the BXSB-Y on autoantibody production, immunopathology, and survival was assessed. We found that the CBA/J.BXSB-Y mice showed few differences from control CBA/J males. In contrast, NZW.BXSB-Y males had accelerated renal and cardiac disease and early death, resembling that previously reported for (NZW X BXSB)F1 mice. NZB.BXSB-Y males had accelerated anti-erythrocyte autoantibodies but not accelerated anti-DNA. They lived almost as long as NZB mice. The presence of the BXSB-Y in all of the consomic mice was confirmed by crossing the consomic mice with BXSB females and demonstrating accelerated disease in the male offspring. This study demonstrates that the BXSB-Y chromosome autoimmune accelerating factor does not act alone but operates through other genes, and that the effects on different genetic backgrounds are different. The studies have implications for human lupus; they also provide a basis for future molecular biology studies of the BXSB-Y and the genes upon which it acts.

Systemic lupus erythematosus: delineation of subpopulations by clinical, serologic, and T cell subset analysis.

Patients with systemic lupus erythematosus (SLE) (n = 194) were analyzed for correlation of clinical features. In addition, the proportions of the two major T cell subsets were determined in 87 subjects. Two patient subgroups were discerned: one in which severe renal disease, leukopenia, and thrombocytopenia predominated, and a second in which sicca syndrome and involvement of the central nervous system, lungs and muscle occurred. The ratio of T helper/inducer to T suppressor/cytotoxic cells was reduced in the first group and increased in the second. We conclude that SLE does not comprise a single disease entity, but rather represents a number of syndromes with overlapping clinical features. The correlation of clinical symptoms with the proportions of circulating T cell subsets suggests that several immunologic mechanisms may underlie the various types of SLE.

Effect of the BXSB Y chromosome accelerating gene on autoantibody production.

The Y chromosome of the BXSB mouse is able to accelerate and adversely alter the autoimmune disease of inbred BXSB mice and in male F1 hybrids. In order to further study the effects of the BXSB Y chromosome, we developed three inbred congenic strains, each bearing the BXSB Y: CBA/J.BXSB-Y, NZW.BXSB-Y, and NZB.BXSB-Y. The BXSB Y did not induce anti-DNA or anti-red blood cell (RBC) autoantibodies in either CBA/J or NZW congenic strains. Thus, it is an accelerating rather than an inducing factor. NZB.BXSB-Y congenic mice had accelerated anti-RBC but not anti-DNA. Studies of recombinant inbred by BXSB F1 mice indicated that the BXSB Y did not act to promote the activity of the NZB gene underlying anti-DNA. These and studies of (BXSB X NZB.BXSB-Y) F1 mice suggested that BXSB autosomal genes are required for the full anti-DNA accelerating activity of the BXSB Y. These mice provide a basis for future molecular genetic studies of the BXSB Y.

The human autologous mixed lymphocyte reaction. II. Analysis of activation and proliferation.

In this study, we have used cell cycle analysis as an independent measure of proliferation and the 4F2 marker to enumerate activated T cells. T-cell proliferation increased gradually throughout the 7-day culture. The degree of proliferation correlated very strongly (r = 0 . 827, p less than 10(-4)) with the degree of T-cell activation as demonstrated by the expression of the 4F2 marker. However, many more T cells became activated during the AMLR than were proliferating. Thymidine incorporation correlated well (r = 0.956, p less than 10(-4)) with numbers of proliferating cells as determined by cell cycle analysis. Adherent cells (M phi) induced fewer T cells to express 4F2 and to proliferate than did (B + null) cells. However, proportionately, M phi induced much more activation than proliferation in comparison to (B + null) cells. Additional analyses of cell cycle and the 4F2 marker for activated cells indicated that a very small percentage of responder T cells (less than 1%) respond initially to signals from autologous non-T cells. Moreover, there is a three-day delay before substantial proliferation and activation takes place, providing time for amplification and suppressive regulatory processes. Ultimately, between 5 and 30% of the initial T cells are capable of proliferating in the AMLR and up to 90% of the cells may become activated. Thus, many cells become activated (and are therefore capable of secreting immune regulatory factors or otherwise participating in immune responses) than proliferate. These results provide a basis for analysing defects in the AMLR in association with various disease states.

Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice.

MRL/lpr and NZB X NZW F1 mice were neonatally thymectomized or treated with androgens from 2 weeks of age, and their natural histories were studied. Neonatal thymectomy of MRL/lpr mice led to marked reduction in the usual massive lymphadenopathy as well as significant reduction in antibodies to native DNA and prolonged survival. In contrast, neonatal thymectomy of NZB X NZW F1 mice led to accelerated disease. Androgen therapy of both mice led to reduced anti-DNA and prolonged survival. This occurred in the MRL/lpr mice without significant reduction in lymphadenopathy. Taken together, these studies suggest that different T cell abnormalities may underlie the development of autoimmunity in MRL/lpr and NZB X NZW F1 mice, but that disease may be expressed through a common androgen-sensitive pathway.